Cheyne-Stokes respiration (CSR) is associated with increased morbidity and mortality in patients with congestive heart failure (CHF). We have found that increases in carotid body (CB) chemoreflex function occur early in the development of CHF, but it is not known if this CB chemoreflex sensitization contributes to the development of CSR. It is also unknown whether pre-existing sleep apnea (SA) aggravates the CB chemoreflex sensitization and CSR that occur in CHF. If so, the compound effects of SA and CHF on CB function would be expected to heighten hyperactivation of sympathetic outflow and deterioration of left ventricular (LV) function. I will determine whether augmented CB chemoreceptor activity is responsible for the development CSR and what role the endothelial flow-sensitive transcription factor Kruppel-like factor 2 (KLF2) plays in this process in a pacing-induced model of CHF in rabbits. I will chronically measure diaphragm EMG (to assess breathing effort/pattern) and renal sympathetic nerve activity (RSNA) at rest via implanted telemetry electrodes, and acute RSNA and ventilatory responses to activation of the CB and central chemoreflexes via brief exposure to isocapnic hypoxia and hyperoxic hypercapnia, respectively. Left ventricular (LV) function will be quantified via regular echocardiography. These measures will allow me to identify the presence of CSR, and the degree of sympathetic activation, chemoreflex sensitization, and LV dysfunction as pacing progresses. In order to determine the role of the CB chemoreflex and KLF2 in these effects, we will use adenoviral transgenic intervention specifically targeted to the CB to normalize KLF2 expression in the CB and assess its impact on CB chemoreflex function, sympathetic nerve activity and CSR during CHF. These studies will quantify the temporal relationship between changes in CB chemoreflex sensitivity and development of CSR during the progression of LV dysfunction, as well as determining the importance of the sensitization of the CB chemoreceptor input to this phenomenon and the role played by KLF2 in these changes. Secondly, I will determine whether exposure to chronic intermittent hypoxia (CIH) prior to and during pacing further exacerbates any identified derangement in KLF2 function in the CB, CSR development, RSNA activation, and LV dysfunction. For this aim I will use methodology as above, however I will incorporate exposure to CIH prior to and during the pacing protocol. These studies will quantify the effect of combined CIH-pacing on KLF2 expression, CB sensitivity, resting RSNA, and CSR development, and determine if CIH hastens the progression and degree of LV dysfunction during pacing. Importantly, the studies will document the role of KLF2 in the pathophysiological sequelae of hyperactivation of the CB that occurs in CHF and CIH. The studies outlined here will advance the applicant toward developing a transitional grant and independence to study the role of endothelial factors in neural control of cardio-respiratory function in disease states. PUBLIC HEALTH RELEVANCE: Sleep-related breathing disorders such as Cheyne-Stokes respiration (CSR) and sleep apnea (SA) are highly prevalent in patients with congestive heart failure, and are associated with increased morbidity and mortality, and decreased quality of life. Addressing mechanisms by which CSR and SA may contribute to deterioration of cardiac function is relevant to the development of more effective treatment for this condition.